Definition Change and Update of Clinical Guidelines for Interstitial Cystitis and Bladder Pain Syndrome.

The clinical guidelines for interstitial cystitis (IC) and bladder pain syndrome (BPS) have been revised by updating our previous guidelines. The symptoms of IC and BPS, collectively called as hypersensitive bladder (HSB) symptoms, are virtually indistinguishable between IC and BPS; however, IC and BPS should be considered as a separate entity of disorders. We define IC as a bladder disease with Hunner lesions, usually associated with HSB symptoms and bladder inflammation, and BPS as a condition with HSB symptoms in the absence of Hunner lesions and any confusable diseases. Pathophysiology totally differs between IC and BPS. IC involves immunological inflammation probably resulting from autoimmunity, while BPS is associated with the interaction of multiple factors such as neurogenic inflammation, exogenous substances, urothelial defects, psychological stress, and neural hyperactivity. Histopathology also differs between IC and BPS. IC is associated with severe inflammation of the whole bladder accompanied by plasma cell infiltration and urothelial denudation, while BPS shows little pathological changes. Management should begin with a differential diagnosis of IC or BPS, which would require cystoscopy to determine the presence or absence of Hunner lesions. The patients should be treated differently based on the diagnosis following the algorithm, although pain management would be common to IC and BPS. Clinical studies are also to be designed and analyzed separately for IC and BPS.

Using Urine Biomarkers to Differentiate Bladder Dysfunctions in Women with Sensory Bladder Disorders.

Sensory bladder disorders encompass several distinct conditions with overlapping symptoms, which pose diagnostic challenges. This study aimed to evaluate urine biomarkers for differentiating between various sensory bladder disorders, including non-Hunner's interstitial cystitis (NHIC), detrusor overactivity (DO), hypersensitive bladder (HSB), and urodynamically normal women. A retrospective analysis of 191 women who underwent a videourodynamic study (VUDS) was conducted, with some also receiving cystoscopic hydrodistention to confirm the presence of NHIC. Participants were categorized into four groups: DO (n = 51), HSB (n = 29), NHIC (n = 81), and normal controls (n = 30). The urine levels of inflammatory and oxidative stress biomarkers were measured. The DO patients exhibited elevated IP-10 levels, while the HSB patients had decreased TAC and 8-OHdG levels. The NHIC patients showed lower IL-2 and higher TNF-α levels. A TNF-α ≥ 1.05 effectively identified NHIC, with an AUROC of 0.889, a sensitivity of 98.8%, and a specificity of 81.3%. An IP-10 ≥ 6.31 differentiated DO with an AUROC of 0.695, a sensitivity of 56.8%, and a specificity of 72.3%. An 8-OHdG ≤ 14.705 and a TAC ≤ 528.7 identified HSB with AUROCs of 0.754 and 0.844, respectively. The combination of 8-OHdG and TAC provided an AUROC of 0.853 for HSB. These findings suggest that TNF-α, IP-10, TAC, 8-OHdG, and IL-2 are promising non-invasive biomarkers for distinguishing between these conditions, which may improve diagnosis and management.

[Pelvic floor muscle training combined with electroacupuncture for bladder dysfunction after incomplete spinal cord injury: a randomized controlled trial].

OBJECTIVE: To observe the efficacy of pelvic floor muscle training combined with electroacupuncture (EA) for bladder dysfunction after incomplete spinal cord injury (SCI). METHODS: Ninety patients with bladder dysfunction after incomplete SCI were randomly divided into an EA group (30 cases), a pelvic floor muscle training group (30 cases, 1 case dropped out), and a combined group (30 cases, 1 case dropped out). All groups received routine rehabilitation. The EA group received EA at Zhongji (CV 3), Guanyuan (CV 4), Mingmen (GV 4), Yaoyangguan (GV 3), bilateral Shenshu (BL 23), Ciliao (BL 32), and Pangguangshu (BL 28), with continuous waves at frequency of 100 Hz, and the needles were retained for 30 min, once daily, 6 times a week for 6 weeks. The pelvic floor muscle training group underwent pelvic floor muscle training two times a day, for 6 weeks. The combined group received both EA and pelvic floor muscle training. The daily average number of urinations, daily average number of urinary leakages, urodynamic indexes (residual urine volume, maximum bladder capacity, bladder compliance, and maximum urine flow rate), and generic quality of life inventory-74 (GQOLI-74) were compared before and after treatment in each group. RESULTS: Compared before treatment, the daily average number of urinations and urinary leakages were decreased (P<0.05), residual urine volume, maximum bladder capacity, and bladder compliance were reduced (P<0.05), and maximum urine flow rate and GQOLI-74 scores were increased (P<0.05) after treatment in all groups. After treatment, the combined group showed greater differences in the daily average number of urinations, daily average number of urinary leakages, residual urine volume, maximum bladder capacity, bladder compliance, maximum urine flow rate, and GQOLI-74 score compared to the EA group and the pelvic floor muscle training group (P<0.05). There was no statistically significant differences in the changes in these indexes between the EA group and the pelvic floor muscle training group (P>0.05). CONCLUSION: Pelvic floor muscle training combined with EA can effectively alleviate urination problems in patients with bladder dysfunction after incomplete SCI, improve bladder function, and enhance patients' quality of life.

Effect of moxibustion on ATP-sensitive potassium channel (KATP) of bladder in detrusor overactivity rats. / 隔姜隔盐灸"神阙"å¯¹é€¼å°¿è‚Œè¿‡åº¦æ´»åŠ¨å¤§é¼ è†€èƒ±ATP敏感性钾离子通道的影响.

OBJECTIVES: To observe the effect of ginger-salt-partitioned moxibustion on ATP-sensitive potassium (KATP) channel of bladder in detrusor overactivity (DO) rats. METHODS: Female SD rats were randomly divided into sham operation, model, moxibustion and antagonist groups (n=9 in each group). Thorax (T) 10 spinal cord transection was performed by surgery. Ginger-salt partitioned moxibustion was applied to "Shenque" (CV8) for 3 cones, once daily for 14 consecutive days. Rats of the antagonist group were intraperitoneally injected with KATP channel specific antagonist glibenclamide (10 µg·kg-1·d-1) once daily for 14 consecutive days. Urodynamic tests were performed after treatment. The distribution and expression of KATP channel tetrameric subunit (SUR2B) in the bladder of rats was observed by immunofluorescence. The protein and mRNA expression levels of SUR2B in bladder tissue were detected by Western blot and qPCR respectively. RESULTS: Compared with the sham operation group, rats of the model group showed intensive and large phasic contractions of the detrusor during bladder filling, the frequency and amplitude of phasic contractions of the detrusor 5 min before leakage were significantly increased (P<0.001)；the voiding threshold pressure was significantly decreased (P<0.001)；the bladder perfusion volume was increased (P<0.001)；the SUR2B protein and mRNA expression in bladder tissue were significantly reduced (P<0.001). Compared with the model group and the antagonist group, the above-mentioned indicators in the moxibustion group were all reversed (P<0.01, P<0.001, P<0.05). CONCLUSIONS: Ginger-salt partitioned moxibustion can reduce the frequency and amplitude of detrusor phase contraction during bladder filling and prolong the time of first phase contraction in DO rats, which may be associated with up-regulating the expression level of KATP channel protein and mRNA, promoting the outflow of potassium ions, and inhibiting the inflow of calcium ions, thus improve the stability of detrusor during storage.

Comparative analysis of surgical prognostic between HIC and NHIC patients after cystoscopy with hydrodistention.

This study aims to clarify the pathogenic mechanism of interstitial cystitis (IC), which has led to uncertainty in its diagnosis and treatment. We examined data from 18 interstitial cystitis with Hunner lesions (HIC) and 18 interstitial cystitis without Hunner lesions (NHIC) patients, including their clinical information, urodynamic test results, and maximum bladder capacity. A 1-year follow-up tracked disease progression. Postoperative recovery showed that HIC patients experienced significantly greater improvements in Visual Analog Scale pain scores compared to NHIC patients (P = .0049). This trend continued at the 6-month mark (P = .0056). Over the 1-year follow-up, NHIC patients exhibited a statistically significant improvement in Pain and Urgency/Frequency scores, while HIC patients had a gradual overall score increase from preoperative to postoperative stages. However, no significant differences were observed in either group at 1 year postoperatively compared to preoperative scores. This study revealed distinct differences between HIC and NHIC patients, including reduced bladder volumes and more severe nociceptive pain in HIC patients. Early analgesic interventions effectively alleviated discomfort in HIC patients. The combination of cystoscopic hydrodistention and water dilatation was highly effective in relieving pain symptoms in HIC patients but increased the risk of recurrence, necessitating recurrent bladder infusion and timely therapeutic adjustments. In contradiction to prior paradigms, the surgical intervention of cystoscopic water hydrodistention also yielded favorable outcomes among NHIC patients.

PDE5 inhibitor potentially improves polyuria and bladder storage and voiding dysfunctions in type 2 diabetic rats.

PURPOSE: Bladder dysfunction associated with type 2 diabetes mellitus (T2DM) includes urine storage and voiding disorders. We examined pathological conditions of the bladder wall in a rat T2DM model and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil. MATERIALS AND METHODS: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats were used as the T2DM and control groups, respectively. Tadalafil was orally administered for 12 weeks. Micturition behavior was monitored using metabolic cages, and bladder function was evaluated by cystometry. Bladder blood flow was evaluated by laser speckle imaging, and an organ bath bladder distention test was used to measure adenosine triphosphate (ATP) release from the bladder urothelium. The expression levels of vesicular nucleotide transporter (VNUT), hypoxia markers, pro-inflammatory cytokines and growth factors in the bladder wall were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Bladder wall contractions in response to KCl and carbachol were monitored using bladder-strip tests. RESULTS: With aging, OLETF rats had higher micturition frequency and greater urine volume than LETO rats. Although bladder capacity was not significantly different, non-voiding bladder contraction occurred more frequently in OLETF rats than in LETO rats. Bladder blood flow was decreased and ATP release was increased with higher VNUT expression in OLETF rats than in LETO rats. These effects were suppressed by tadalafil administration, with accompanying decreased HIF-1α, 8-OHdG, IL-6, TNF-α, IGF-1, and bFGF expression. The impaired contractile responses of bladder strips to KCl and carbachol in OLETF rats with aging were restored by tadalafil administration. CONCLUSIONS: The T2DM rats had polyuria, increased ATP release induced by decreased bladder blood flow and impaired contractile function. PDE5 inhibition improved these changes and may prevent T2DM-associated urinary frequency and bladder storage and voiding dysfunctions.

Reducing pain by improving brain and muscle activity with motor cortical neuromodulation in women with interstitial cystitis/bladder pain syndrome: a study protocol for a randomized controlled trial.

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain condition creating a wide range of urologic and pain symptoms. There is currently limited evidence to understand the mechanisms of IC/BPS. There have been recent studies suggesting that altered function in brain motor areas, particularly the supplementary motor cortex (SMA), relates to altered bladder sensorimotor control and may play an important role in IC/BPS. This study aims to provide evidence that non-invasive stimulation targeting the motor cortex may help reduce IC/BPS pain, as well as better understand the neural mechanism by which this stimulation targets neuromuscular dysfunction. This study is a two-group quadruple-blinded randomized controlled trial (RCT) of active vs. sham repetitive transmagnetic stimulation (rTMS). In addition, our study will also include functional magnetic resonance imaging (fMRI), pelvic floor electromyography (EMG), pelvic exam, and outcome measures and questionnaires to further study outcomes. ETHICS AND DISSEMINATION: All aspects of the study were approved by the Institutional Review Board of the University of Southern California (protocol HS-20-01021). All participants provided informed consent by the research coordinator/assistants. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences. TRIAL REGISTRATION: ClinicalTrials.gov NCT04734847. Registered on February 1, 2021.

Optimization of activity-driven event detection for long-term ambulatory urodynamics.

Lower urinary tract dysfunction (LUTD) is a debilitating condition that affects millions of individuals worldwide, greatly diminishing their quality of life. The use of wireless, catheter-free implantable devices for long-term ambulatory bladder monitoring, combined with a single-sensor system capable of detecting various bladder events, has the potential to significantly enhance the diagnosis and treatment of LUTD. However, these systems produce large amounts of bladder data that may contain physiological noise in the pressure signals caused by motion artifacts and sudden movements, such as coughing or laughing, potentially leading to false positives during bladder event classification and inaccurate diagnosis/treatment. Integration of activity recognition (AR) can improve classification accuracy, provide context regarding patient activity, and detect motion artifacts by identifying contractions that may result from patient movement. This work investigates the utility of including data from inertial measurement units (IMUs) in the classification pipeline, and considers various digital signal processing (DSP) and machine learning (ML) techniques for optimization and activity classification. In a case study, we analyze simultaneous bladder pressure and IMU data collected from an ambulating female Yucatan minipig. We identified 10 important, yet relatively inexpensive to compute signal features, with which we achieve an average 91.5% activity classification accuracy. Moreover, when classified activities are included in the bladder event analysis pipeline, we observe an improvement in classification accuracy, from 81% to 89.0%. These results suggest that certain IMU features can improve bladder event classification accuracy with low computational overhead.Clinical Relevance: This work establishes that activity recognition may be used in conjunction with single-channel bladder event detection systems to distinguish between contractions and motion artifacts for reducing the incorrect classification of bladder events. This is relevant for emerging sensors that measure intravesical pressure alone or for data analysis of bladder pressure in ambulatory subjects that contain significant abdominal pressure artifacts.

Local Injection of Stem Cells Can Be a Potential Strategy to Improve Bladder Dysfunction after Outlet Obstruction in Rats.

This study investigates whether hAFSCs can improve bladder function in partial bladder outlet obstruction (pBOO) rats by targeting specific cellular pathways. Thirty-six female rats were divided into sham and pBOO groups with and without hAFSCs single injection into the bladder wall. Cystometry, inflammation/hypoxia, collagen/fibrosis/gap junction proteins, and smooth muscle myosin/muscarinic receptors were examined at 2 and 6 weeks after pBOO or sham operation. In pBOO bladders, significant increases in peak voiding pressure and residual volume stimulated a significant upregulation of inflammatory and hypoxic factors, TGF-ß1 and Smad2/3. Collagen deposition proteins, collagen 1 and 3, were significantly increased, but bladder fibrosis markers, caveolin 1 and 3, were significantly decreased. Gap junction intercellular communication protein, connexin 43, was significantly increased, but the number of caveolae was significantly decreased. Markers for the smooth muscle phenotype, myosin heavy chain 11 and guanylate-dependent protein kinase, as well as M2 muscarinic receptors, were significantly increased in cultured detrusor cells. However, hAFSCs treatment could significantly ameliorate bladder dysfunction by inactivating the TGFß-Smad signaling pathway, reducing collagen deposition, disrupting gap junctional intercellular communication, and modifying the expressions of smooth muscle myosin and caveolae/caveolin proteins. The results support the potential value of hAFSCs-based treatment of bladder dysfunction in BOO patients.

Onset of Spontaneous Filling and Voiding Cycles in the Lower Urinary Tract: A Modeling Study.

Spontaneous filling and voiding cycles represent a key dynamical feature of the healthy lower urinary tract. Some urinary tract dysfunctions, such as over-flow incontinence, may alter the natural occurrence of these cycles. As the function of the lower urinary tract arises from the interplay of a multitude of factors, it is difficult to determine which of them can be modulated to regain spontaneous cycles. In this study, we develop a mathematical model of the lower urinary tract that can capture filling and voiding cycles in the form of periodic solutions of a system of ordinary differential equations. After experimental validation, we utilize this model to study the effect that several physiological quantities have on the onset of cycles. We find that some parameters have an associated numerical threshold that determines whether the system exhibits healthy cycles or settles in a state of constant overflow.

Isolated bladder training or in combination with other therapies to improve overactive bladder symptoms: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Bladder training (BT), the maintenance of a scheduled voiding regime at gradually adjusted intervals, is a common treatment for overactive bladder (OAB). OBJECTIVES: To assess the effects of isolated BT and/or in combination with other therapies on OAB symptoms. METHODS: A systematic review of eight databases was conducted. After screening titles and abstracts, full texts were retrieved. Cochrane RoB 2 and the GRADE approach were used. RESULTS: Fourteen RCTs were included: they studied isolated BT (n = 11), BT plus drug treatment (DT; n = 5), BT plus intravaginal electrical stimulation (IVES; n = 2), BT plus biofeedback and IVES (n = 1), BT plus pelvic floor muscle training and behavioral therapy (n = 2), BT plus percutaneous tibial nerve stimulation, and BT plus transcutaneous tibial nerve stimulation (n = 1). In a meta-analysis of short-term follow-up data, BT plus IVES resulted in greater improvement in nocturia (mean difference [MD]: 0.89, 95% CI: 0.5, 1.20), urinary incontinence (UI; MD: 1.93, 95% CI: 1.32, 2.55), and quality of life (QoL; MD: 4.87, 95% CI: 2.24, 7.50) than isolated BT, while DT and BT improved UI (MD: 0.58, 95% CI: 0.23, 0.92) more than isolated BT. CONCLUSION: In the short term, BT plus IVES improves the OAB symptoms of nocturia and UI while improving QoL. The limited number of RCTs and heterogeneity among them provide a low level of evidence, making the effect of BT on OAB inconclusive, which suggests that new RCTs should be performed.

Urinary dysfunction after spinal cord injury: Comparing outcomes after thoracic spinal transection and contusion in the rat.

Spinal cord injury (SCI) above the lumbosacral spinal cord induces loss of voluntary control over micturition. Spinal cord transection (SCT) was the gold standard method to reproduce SCI in rodents, but its translational value is arguable and other experimental SCI methods need to be better investigated, including spinal cord contusion (SCC). At present, it is not fully investigated if urinary impairments arising after transection and contusion are comparable. To explore this, we studied bladder-reflex activity and lower urinary tract (LUT) and spinal cord innervation after SCT and different severities of SCC. Severe-contusion animals presented a longer spinal shock period and the tendency for higher residual volumes, followed by SCT and mild-contusion animals. Urodynamics showed that SCT animals presented higher basal and peak bladder pressures. Immunostaining against growth-associated protein-43 (GAP43) and calcitonin gene-related peptide (CGRP) at the lumbosacral spinal cord demonstrated that afferent sprouting is dependent on the injury model, reflecting the severity of the lesion, with a higher expression in SCT animals. In LUT organs, the expression of GAP43, CGRP cholinergic (vesicular acetylcholine transporter (VAChT)) and noradrenergic (tyrosine hydroxylase (TH)) markers was reduced after SCI in the LUT and lumbosacral cord, but only the lumbosacral expression of VAChT was dependent on the injury model. Overall, our findings demonstrate that changes in LUT innervation and function after contusion and transection are similar but result from distinct neuroplastic processes at the lumbosacral spinal cord. This may impact the development of new therapeutic options for urinary impairment arising after spinal cord insult.

Intraoperative pelvic neuromonitoring based on bioimpedance signals: a new method analyzed on 30 patients.

PURPOSE: Increasing importance has been attributed in recent years to the preservation of the pelvic autonomic nerves during rectal resection to achieve better functional results. In addition to improved surgical techniques, intraoperative neuromonitoring may be useful. METHODS: This single-arm prospective study included 30 patients who underwent rectal resection performed with intraoperative neuromonitoring by recording the change in the tissue impedance of the urinary bladder and rectum after stimulation of the pelvic autonomic nerves. The International Prostate Symptom Score, the post-void residual urine volume and the Low Anterior Resection Syndrome Score (LARS score) were assessed during the 12-month follow-up period. RESULTS: A stimulation-induced change in tissue impedance was observed in 28/30 patients (93.3%). In the presence of risk factors such as low anastomosis, neoadjuvant radiotherapy and a deviation stoma, an average increase of the LARS score by 9 points was observed 12 months after surgery (p = 0,04). The function of the urinary bladder remained unaffected in the first week (p = 0,7) as well as 12 months after the procedure (p = 0,93). CONCLUSION: The clinical feasibility of the new method for pelvic intraoperative neuromonitoring could be verified. The benefits of intraoperative pelvic neuromonitoring were particularly evident in difficult intraoperative situations with challenging visualization of the pelvic nerves.

Intravesical Botulin Toxin-A Injections for Neurogenic Bladder Dysfunction in Children: Summary Update on Last 10 Years of Research.

Neurogenic bladder dysfunction (NB) represents a challenge in pediatric urology. Intravesical botulin toxin-A (BTX-A) bladder injection is part of the armamentarium for the treatment of this condition, usually after failed first-line medical strategies and before the escalation to more invasive options such as neuromodulation or augmented cystoplasty in severe cases. However, there is still a lack of consensus about the appropriate treatment modality for the pediatric population. A review of the last 10 years' research was performed on the PubMed database by two authors. Articles doubly selected and meeting the inclusion criteria were collected and analyzed for their study type, demographics, neurological disease(s) at diagnosis, BTX-A treatment modality and duration, previous treatment, clinical and urodynamic parameters, adverse events, outcomes, and follow-ups. A total of 285 studies were initially selected, 16 of which matched the inclusion criteria. A cohort of 630 patients was treated with BTX-A at a median age of 9.7 years, 40% of which had a diagnosis of myelomeningocele. The results of the selected publications show the overall efficacy and safety of BTX-A injections in children and confirmed BTX-A as a valuable strategy for NB treatment in pediatric population. Nevertheless, up to now, the literature on this topic offers scarce uniformity among the published series and poor protocol standardization.

In Silico Electrophysiological Investigation of Transient Receptor Potential Melastatin-4 Ion Channel Biophysics to Study Detrusor Overactivity.

Enhanced electrical activity in detrusor smooth muscle (DSM) cells is a key factor in detrusor overactivity which causes overactive bladder pathological disorders. Transient receptor potential melastatin-4 (TRPM4) channels, which are calcium-activated cation channels, play a role in regulating DSM electrical activities. These channels likely contribute to depolarizing the DSM cell membrane, leading to bladder overactivity. Our research focuses on understanding TRPM4 channel function in the DSM cells of mice, using computational modeling. We aimed to create a detailed computational model of the TRPM4 channel based on existing electrophysiological data. We employed a modified Hodgkin-Huxley model with an incorporated TRP-like current to simulate action potential firing in response to current and synaptic stimulus inputs. Validation against experimental data showed close agreement with our simulations. Our model is the first to analyze the TRPM4 channel's role in DSM electrical activity, potentially revealing insights into bladder overactivity. In conclusion, TRPM4 channels are pivotal in regulating human DSM function, and TRPM4 channel inhibitors could be promising targets for treating overactive bladder.

Genital Pain and the Spectrum of Bladder-Related Symptoms: Findings from the Prevention of Lower Urinary Tract Symptoms Research Consortium RISE FOR HEALTH Study, USA.

INTRODUCTION AND HYPOTHESIS: Women with vulvovaginal or genital pain more commonly experience interstitial cystitis/bladder pain syndrome (IC/BPS) and urinary tract infections. However, the relationship between genital pain and bladder health is lacking. METHODS: Women in the Prevention of Lower Urinary Tract Symptoms Consortium's RISE FOR HEALTH population-based study answered questions about bladder health globally, and across nine bladder health domains of holding, efficacy, social-occupation, physical activity, intimacy, travel, emotion, perception, and freedom. Bladder function was assessed across six indices including urinary frequency, sensation, continence, comfort, emptying, and dysbiosis (e.g., urinary tract infections). Participants were grouped by no pain beyond transitory events (i.e., minor headaches, toothaches, or sprains), nongenital-related pain only, and any genital pain using a validated pain diagram. Mean adjusted scores and indices were compared using general linear modelling. RESULTS: Of 1,973 eligible women, 250 (12.7%) reported genital pain, 609 (30.9%) reported nongenital pain only, and 1,114 (56.5%) reported no pain. Women with any genital pain had lower (worse) adjusted mean scores across all bladder health scales (BHS; BHS global adjusted mean 47.5; 95% CI 40.8-54.1), compared with those with nongenital pain only (53.7; 95% CI 47.6-59.8), and no pain (59.3; 95% CI 53.3-65.4). Similarly, adjusted mean total Bladder Functional Index scores were lower for those with genital pain (63.1; 95% CI 58.4-67.9) compared with nongenital pain (72.1; 95% CI 67.7-76.5) and no pain (77.4; 95% CI 73.0-81.8). CONCLUSIONS: Heightened awareness of the relationship between genital pain and bladder health should prompt clinicians caring for women with genital pain to assess bladder health and function.

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome.

Rare early-onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders, whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

Model-based analysis of the acute effects of transcutaneous magnetic spinal cord stimulation on micturition after spinal cord injury in humans.

AIM: After spinal cord injuries (SCIs), patients may develop either detrusor-sphincter dyssynergia (DSD) or urinary incontinence, depending on the level of the spinal injury. DSD and incontinence reflect the loss of coordinated neural control among the detrusor muscle, which increases bladder pressure to facilitate urination, and urethral sphincters and pelvic floor muscles, which control the bladder outlet to restrict or permit bladder emptying. Transcutaneous magnetic stimulation (TMS) applied to the spinal cord after SCI reduced DSD and incontinence. We defined, within a mathematical model, the minimum neuronal elements necessary to replicate neurogenic dysfunction of the bladder after a SCI and incorporated into this model the minimum additional neurophysiological features sufficient to replicate the improvements in bladder function associated with lumbar TMS of the spine in patients with SCI. METHODS: We created a computational model of the neural circuit of micturition based on Hodgkin-Huxley equations that replicated normal bladder function. We added interneurons and increased network complexity to reproduce dysfunctional micturition after SCI, and we increased the density and complexity of interactions of both inhibitory and excitatory lumbar spinal interneurons responsive to TMS to provide a more diverse set of spinal responses to intrinsic and extrinsic activation of spinal interneurons that remains after SCI. RESULTS: The model reproduced the re-emergence of a spinal voiding reflex after SCI. When we investigated the effect of monophasic and biphasic TMS at two frequencies applied at or below T10, the model replicated the improved coordination between detrusor and external urethral sphincter activity that has been observed clinically: low-frequency TMS (1 Hz) within the model normalized control of voiding after SCI, whereas high-frequency TMS (30 Hz) enhanced urine storage. CONCLUSION: Neuroplasticity and increased complexity of interactions among lumbar interneurons, beyond what is necessary to simulate normal bladder function, must be present in order to replicate the effects of SCI on control of micturition, and both neuronal and network modifications of lumbar interneurons are essential to understand the mechanisms whereby TMS reduced bladder dysfunction after SCI.

Effect of photobiomodulation on lower urinary tract dysfunction in rat cystitis model.

OBJECTIVE: Photobiomodulation selectively controls the activity of the sensory nervous system associated with A-delta and C fibers. Hypersensitivity involving the afferent A-delta and C fibers occurs in cystitis and decreases urinary function. This study aimed to investigate the effect of photobiomodulation on urinary storage dysfunction and voiding functions in cystitis model rats. METHODS: We prepared the rat cystitis model. Under anesthesia, a cannula was connected to the bladder via a ventral incision. 0.3% acetic acid or saline was injected into the bladder. Continuous cystometry was performed, measuring bladder pressure and voiding urine volume with rats freely mobile. Laser irradiation was applied to the L6 lumbosacral intervertebral foramen using an 830 nm laser. Residual urine was extracted post-cystometry. RESULTS: In the rat cystitis model groups, there was a significant decrease in the voiding interval and volume compared to the group receiving normal saline infusion. After sham or laser irradiation, only the group with laser irradiation showed a significant increase in voiding interval (217%, p = 0.0002) and voiding volume (192%, p = 0.0012) in the parameters of storage dysfunction. The basal pressure, intravesical pressure, and residual urine volume remained unchanged in all groups before and after irradiation. CONCLUSIONS: This study indicates that photobiomodulation may improve urine storage dysfunction without exacerbating voiding function in a rat model of cystitis. Thus, photobiomodulation may be a new treatment option for the hypersensitivity and detrusor overactivity caused by cystitis.